Delavirdine and PNU-140690

In October, Pharmacia & Upjohn called a small community meeting to report preliminary data from a new study of a triple regimen containing delavirdine and to discuss their development plans for their protease inhibitor (PNU-140690). The delavirdine study compared AZT+3TC+delavirdine, AZT+3TC, and delavirdine+AZT. Although the study participants were not AZT naive they were required to have less than 6 months AZT experience. The study has not yet been presented at an AIDS scientific meeting.

Following is an interim analysis after 32 weeks of a 1 year study.

DLV+AZT/3TC Baseline Week 8 Week 16 Week 32

HIV RNA (copies/ml) 31,500

CD4• 353 +78 +86 +96

Prior AZT Use

< 6 mos 20%

none 80%

VL¯ (40 copies/ml) -2.4 log -2.2 log -2.0 log

VL¯ (400 copies/ml) -1.8 log -1.6 log -1.5 log

% <40 copies/ml 43% 55% 50%

% <400 copies/ml 80% 74% 63%

N 117 84 72 45

Upjohn is planning additional studies of multi-drug combinations including protease inhibitors and delavirdine.

Viral Load Reductions and CD4 Increases from Baseline for AZT/3TC and AZT/DLV*

CD4• VL¯ 40 copy test VL¯ 400 copy test %<40 copies/ml

AZT/3TC wk 4 peak RNA - -2.0 log na 15%

wk 8 - -1.7 log na -

wk 32 +70 -1.3 log na 12%

wk 40 +90 na na na

DLV/AZT

wk 2 peak RNA - -1.6 log na 5%

wk 8 - -0.8 log na -

wk 32 +20 -0.5 log na 0%

wk 40 +30 na na na

* Values are approximations based on close visual observation of line graph charts.

The Upjohn protease inhibitor is in early stages of human testing. PNU-140690 may have a unique resistance profile. The company is planning to evaluate its effectiveness against virus resistance to other protease inhibitors by testing it against resistant virus.

Preliminary interaction when combining with Delavitdine

It is uncertain which doses of the two drugs should be used together. Studies are planned or already ongoing to explore the proper dosing combination of the two drugs. ACTG 359 is for individuals who’ve failed indinavir; it started in November ‘97 and is exploring use 3 and 4 drug regimens including nelfinavir++ delavirdine 600 mg bid; adefovir (new nucleotide) will also be used in this study. Initial interaction (PK) data should be available soon. Upjohn also has a study exploring different dose regimens for using nelfinavir with delavirdine. Two doses of delavirdine (400 or 600 mg tid) will be explored with nelfinavir 750 mg tid in combination with d4T and ddI. Experimenting using drugs before proper dosing is identified can result in either one of two potentially harmful outcomes. The blood concentration of a drug could be too low resulting in resistance developing; or, blood levels of a drug could be too high resulting in toxicities.

Upjohn conducted an initial study exploring interactions between delavirdine and nelfinavir in 24 healthy volunteers. Group A received nelfinavir 750 mg every 8 hrs for 1 week followed by concomitant treatment with nelfinavir 750 mg and delavirdine 400 mg, each every 8 hrs. Group B received delavirdine 400 mg every 8 hrs for 1 week followed by concomitant treatment with delavirdine 400 mg every 8 hrs plus nelfinavir 750 mg every 8 hrs. All doses were taken with food.

Safety. Four out of 24 individuals discontinued the study due to neutropenia. Two subjects experienced serious (grade 3/4) neutropenia as a result of the combination. In each case, the neutropenia resolved after stopping both drugs. Investigators said except for the neutropenia the combination was well tolerated. When using these two drugs together, absolute neutrophil count should be frequently monitored.

Mean Changes in Nelfinavir Pharmacokinetic (blood levels) Values obtained from 12 individuals in group A

NLF alone NLF+DLV Mean Change NLF AUC (ug h/mL, 0-8 hrs) 26 50 +113% (± 25%)

NLF Cmax (ug/mL) 4.2 7.6 +93% (± 24%)

NLF Cmin (ug/mL) 2.2 4.9 +146% (± 37%)

Mean Changes in Delavirdine Pharmacokinetic Values

The following data was obtained from 7 individuals in group B

DLV alone DLV+NLF

DLV AUC (uM h, 0-8) 210 (± 112) 122 (± 24)

DLV Cmax (uM) 32 (± 16) 21 (± 5)

DLV Cmin (uM) 21 (± 13) 10 (± 3)

As you can see, the AUC of delavirdine was reduced by about 40% in this study and the Cmax was reduced by about 34%. The important Cmin, also called the trough, was reduced by about 50%. Delavirdine and nelfinavir concentration data was available for 20 patients in a community practice setting where each received the two drugs at their normally recommended doses for over 1 month. Blood samples were obtained between 6 to 9 hrs after the doses of both drugs. The median Cmin, or trough, concentration of delavirdine was about 40% lower than when taking delavirdine in combination with nucleosides. The reduced Cmin of delavirdine is the reason that a higher 600 mg tid dose of delavirdine will be explored in the clinical study where nelfinavir will be combined with delavirdine, d4T and ddI in 3 and 4 drug combinations. Trough levels will be evaluated. Again, it may be prefferable to wait til proper dosing regimens have been identified before using these combinations.

Preliminary PK of Combining with Delavirdine

A small preliminary interaction study using 12 patients has been conducted. Ten of the 12 individuals had AIDS. The baseline CD4 counts were about 163 with a wide variability among the participants. Participants had prior ritonavir experience of 1 to 12 months. A 600 mg bid of ritonavir was administered for at least 14 days with nucleosides. Delavirdine 400 mg tid was added. There was no group who started with delavirdine and then added ritonavir after steady state of delavirdine was reached. The study used historical PK values of delavirdine, and PK values observed in a previous PK study using a ritonavir 300 mg bid. Based on these previous observations and other information, Upjohn does not expect ritonavir will have a significant effect on delavirdine blood levels.

The ACTG 359 is just beginning. The regimens available in the study include ritonavir+saquinavir+delavirdine or nelfinavir+saquinavir+delavirdine. Adefovir will also be used in the study. In this study delavirdine dosing will be 600 mg bid???. Investigators will analyze interaction data in the initial stage of the study. It is expected that saquinavir should not effect delavirdine blood levels; however, this study will explore the 3 drugs being used together, all of which effect the CYP450 liver enzyme system.

In the interaction (PK) study, delavirdine increased overall ritonavir blood levels by 70%. Following are the effects on specific PK parameters-

RTV alone RTV+DLV Mean increase (range) RTV AUC (ugxhrs/mL, 0-12) 68 111 • 60% (22-90%)

RTV Cmax (ug/mL) 10.7 17.7 • 66% (24-109)

RTV Cmin (ug/mL) 2.6 4.7 • 84% (41-127)

Safety. There was 1 grade 4 elevation of triglycerides; 1 grade 3 elevation of LFTs; 1 grade 1 rash; and 1 grade 2 thrombocytopenia. All of these may have been experienced by one person.

Indinavir + Delavirdine

As explained in NATAP’s July issue of NATAP Reports, delavirdine increases indinavir blood levels. Please refer to that article for detailed discussin. You can contact our office for a copy or read it on our web site. A trial will be conducted exploring two indinavir doses (400 mg tid or 600 mg tid) with 400 mg tid delavirdine. A twice a day dose regimen study is also planned using 800 or1000 mg bid indinavir plus 600 mg bid delavirdine.

PNU 140690 (protease inhibitor)

Upjohn conducted studies of their protease inhibitor and reported the data at ICAAC. Safety, tolerance and were studied in healthy volunteers (n=48) in escalating single doses at doses of 100, 300, 500, 700, 900, 1200, 1600, and 2000 mg.

Investigators characterized PNU 140690 as generally well tolerated for up to the 10 days of study. Gastrointestinal related side effects were the most commonly observed (nausea, diarrhea, vomiting and abdominal cramping). They were mostly mild and occasionally moderate. No serious medical events were reported and no clinically significant lab abnormalities were reported. 140690 showed a modest 30% in the dog and rat and was attributed to limited drug absorption. The AUC of various doses suggest dosing at 3 times per day.

Preclinical studies showed a synergy when 140690 was combined with ritonavir vs ritonavir resistant virus . PNU 140690 was active against ritonavir resistant virus. Combining PNU 140690 with Ritonavir might improve dosing of PNU to twice daily.

On average, PNU concentrations of above 1uM were achieved at or above doses of 900 mg every 8 hrs. Upjohn thinks the resistance profile of PNU may be sufficiently unique to be effective against protease inhibitor resistant virus. In first quater ‘98 they plan to explore this potential by initiating a trial treating individuals who’ve failed indinavir with PNU 140690. Subsequent trials are expected, treating individuals who’ve failed other protease inhibitors.